Editing Benzodiazepine (section)

==Pharmacology==
===Pharmacodynamics===
[[Image:GABAA-receptor-protein-example-en.svg|thumb|class=skin-invert-image|alt=Figure of the GABA<sub>A</sub> receptor complex where the five subunits (two alpha, two beta, and one gamma) are symmetrically arranged in a pentagon shape about a central ion conduction pore. The location of the two GABA binding sites are located between the alpha and beta subunit, while the single benzodiazepine binding site is located between the alpha and gamma subunits.|Schematic diagram of the (α1)<sub>2</sub>(β2)<sub>2</sub>(γ2) GABA<sub>A</sub> receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl<sup>−</sup>) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.]]

Benzodiazepines work by increasing the effectiveness of the endogenous chemical, [[gamma-Aminobutyric acid|GABA]], to decrease the excitability of [[neuron]]s.<ref name="isbn0-12-088397-X">{{cite book |vauthors=Olsen RW, Betz H |veditors=Siegel GJ, Albers RW, Brady S, Price DD |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects |edition=7th |publisher=Elsevier |year=2006 |pages=291–302 |chapter=GABA and glycine |isbn=978-0-12-088397-4 }}</ref> This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

GABA controls the excitability of neurons by binding to the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="isbn0-12-088397-X"/> The GABA<sub>A</sub> receptor is a [[multiprotein complex|protein complex]] located in the [[chemical synapse|synapses]] between neurons. All GABA<sub>A</sub> receptors contain an [[ion channel]] that conducts [[chloride]] ions across neuronal [[cell membrane]]s and two binding sites for the [[neurotransmitter]] gamma-aminobutyric acid (GABA), while a subset of GABA<sub>A</sub> receptor complexes also contain a single binding site for benzodiazepines. Binding of benzodiazepines to this receptor complex does not alter binding of GABA. Unlike other positive [[allosteric modulator]]s that increase ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. This increased chloride ion influx hyperpolarizes the neuron's [[membrane potential]]. As a result, the difference between resting potential and threshold potential is increased and [[action potential|firing]] is less likely.
Different GABA<sub>A</sub> receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct [[biological neural network|neuronal circuits]]. Hence, activation of different GABA<sub>A</sub> receptor subtypes by benzodiazepines may result in distinct pharmacological actions.<ref name="pmid16376150">{{cite journal | vauthors = Rudolph U, Möhler H | title = GABA-based therapeutic approaches: GABA<sub>A</sub> receptor subtype functions | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 18–23 | date = February 2006 | pmid = 16376150 | doi = 10.1016/j.coph.2005.10.003 }}</ref> In terms of the mechanism of action of benzodiazepines, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug at higher doses induces sleep.<ref>{{cite book |vauthors=Puri BK, Tyrer P |title=Sciences Basic to Psychiatry |edition=2nd |year=1998 |publisher=Churchill Livingstone |isbn=978-0-443-05514-0 |pages=155–156 |chapter=Clinical psychopharmacology }}</ref>

The subset of GABA<sub>A</sub> receptors that also bind benzodiazepines are referred to as benzodiazepine receptors (BzR). The GABA<sub>A</sub> receptor is a [[heteromer]] composed of five subunits, the most common ones being two ''α''s, two ''β''s, and one ''γ'' (α<sub>2</sub>β<sub>2</sub>γ1). For each subunit, many subtypes exist (α<sub>1–6</sub>, β<sub>1–3</sub>, and γ<sub>1–3</sub>). GABA<sub>A</sub> receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects.<ref name="pmid8783370">{{cite journal | vauthors = Johnston GA | title = GABA<sub>A</sub> receptor pharmacology | journal = Pharmacology & Therapeutics | volume = 69 | issue = 3 | pages = 173–198 | year = 1996 | pmid = 8783370 | doi = 10.1016/0163-7258(95)02043-8 }}</ref> Benzodiazepines bind at the interface of the α and γ subunits on the GABA<sub>A</sub> receptor. Binding also requires that alpha subunits contain a [[histidine]] amino acid residue, (i.e., [[GABRA1|α<sub>1</sub>]], [[GABRA2|α<sub>2</sub>]], [[GABRA3|α<sub>3</sub>]], and [[GABRA5|α<sub>5</sub>]] containing GABA<sub>A</sub> receptors). For this reason, benzodiazepines show no affinity for GABA<sub>A</sub> receptors containing [[GABRA4|α<sub>4</sub>]] and [[GABRA6|α<sub>6</sub>]] subunits with an [[arginine]] instead of a histidine residue.<ref name="pmid15157182">{{cite journal | vauthors = Wafford KA, Macaulay AJ, Fradley R, O'Meara GF, Reynolds DS, Rosahl TW | title = Differentiating the role of gamma-aminobutyric acid type A (GABA<sub>A</sub>) receptor subtypes | journal = Biochemical Society Transactions | volume = 32 | issue = Pt3 | pages = 553–556 | date = June 2004 | pmid = 15157182 | doi = 10.1042/BST0320553 }}</ref> Once bound to the benzodiazepine receptor, the benzodiazepine [[ligand (biochemistry)|ligand]] locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the [[gamma-aminobutyric acid|GABA]] [[neurotransmitter]]. This increases the frequency of the opening of the associated chloride [[ion channel]] and [[hyperpolarization (biology)|hyperpolarizes]] the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedative and anxiolytic effects. For instance, those ligands with high activity at the α<sub>1</sub> are associated with stronger [[hypnotic]] effects, whereas those with higher affinity for GABA<sub>A</sub> receptors containing α<sub>2</sub> and/or α<sub>3</sub> subunits have good anti-anxiety activity.<ref name="pmid9824848">{{cite journal | vauthors = Hevers W, Lüddens H | title = The diversity of GABA<sub>A</sub> receptors. Pharmacological and electrophysiological properties of GABA<sub>A</sub> channel subtypes | journal = Molecular Neurobiology | volume = 18 | issue = 1 | pages = 35–86 | date = August 1998 | pmid = 9824848 | doi = 10.1007/BF02741459 | s2cid = 32359279 }}</ref>

GABA<sub>A</sub> receptors participate in the regulation of synaptic pruning by prompting microglial spine engulfment.<ref>{{cite journal | vauthors = Afroz S, Parato J, Shen H, Smith SS | title = Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines | journal = eLife | volume = 5 | pages = e15106 | date = May 2016 | pmid = 27136678 | pmc = 4871702 | doi = 10.7554/eLife.15106 | s2cid = 8422877 | title-link = doi | doi-access = free | veditors = Kennedy MB}}</ref> Benzodiazepines have been shown to upregulate microglial spine engulfment and prompt overzealous eradication of synaptic connections.<ref>{{cite journal | vauthors = Shi Y, Cui M, Ochs K, Brendel M, Strübing FL, Briel N, Eckenweber F, Zou C, Banati RB, Liu GJ, Middleton RJ, Rupprecht R, Rudolph U, Zeilhofer HU, Rammes G, Herms J, Dorostkar MM | title = Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO) | journal = Nature Neuroscience | volume = 25 | issue = 3 | pages = 317–329 | date = March 2022 | pmid = 35228700 | doi = 10.1038/s41593-022-01013-9 | s2cid = 247169270 }}</ref> This mechanism may help explain the increased risk of dementia associated with long-term benzodiazepine treatment.<ref>{{cite journal | vauthors = He Q, Chen X, Wu T, Li L, Fei X | title = Risk of Dementia in Long-Term Benzodiazepine Users: Evidence from a Meta-Analysis of Observational Studies | journal = Journal of Clinical Neurology | volume = 15 | issue = 1 | pages = 9–19 | date = January 2019 | pmid = 30375757 | pmc = 6325366 | doi = 10.3988/jcn.2019.15.1.9 }}</ref>

The benzodiazepine class of drugs also interact with [[translocator protein|peripheral benzodiazepine receptors]]. Peripheral benzodiazepine receptors are present in [[peripheral nervous system]] tissues, [[glial cells]], and to a lesser extent the central nervous system.<ref name="pmid12240908">{{cite journal | vauthors = Arvat E, Giordano R, Grottoli S, Ghigo E | title = Benzodiazepines and anterior pituitary function | journal = [[Journal of Endocrinological Investigation]] | volume = 25 | issue = 8 | pages = 735–747 | date = September 2002 | pmid = 12240908 | doi = 10.1007/bf03345110 | s2cid = 32002501 }}</ref> These peripheral receptors are not structurally related or coupled to GABA<sub>A</sub> receptors. They modulate the [[immune system]] and are involved in the body response to injury.<ref name="pmid9504140">{{cite journal | vauthors = Zavala F | title = Benzodiazepines, anxiety and immunity | journal = Pharmacology & Therapeutics | volume = 75 | issue = 3 | pages = 199–216 | date = September 1997 | pmid = 9504140 | doi = 10.1016/S0163-7258(97)00055-7 }}</ref><ref name="pmid9378234">{{cite journal | vauthors = Zisterer DM, Williams DC | title = Peripheral-type benzodiazepine receptors | journal = General Pharmacology | volume = 29 | issue = 3 | pages = 305–314 | date = September 1997 | pmid = 9378234 | doi = 10.1016/S0306-3623(96)00473-9 }}</ref> Benzodiazepines also function as weak [[adenosine reuptake inhibitor]]s. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action.<ref name="pmid16780077">{{cite journal | vauthors = Narimatsu E, Niiya T, Kawamata M, Namiki A | title = [The mechanisms of depression by benzodiazepines, barbiturates and propofol of excitatory synaptic transmissions mediated by adenosine neuromodulation] | language = ja | journal = Masui | volume = 55 | issue = 6 | pages = 684–691 | date = June 2006 | pmid = 16780077 }}</ref> Benzodiazepines have binding sites in the periphery, however their effects on muscle tone is not mediated through these peripheral receptors. The peripheral binding sites for benzodiazepines are present in immune cells and gastrointestinal tract.<ref name="pmid18922233" />

===Pharmacokinetics===
{| class="wikitable sortable" style="float: right; margin-left:15px; text-align:center"
|-
! Benzodiazepine !! Half-life <br />([[prediction interval|range]], hours) !! Speed of onset
|-
| [[Alprazolam]]|| 6–15<ref name=OBrien>{{cite journal |vauthors=O'brien CP |title=Benzodiazepine use, abuse, and dependence |journal=The Journal of Clinical Psychiatry |volume=66 |issue=Suppl 2 |pages=28–33 |year=2005 |pmid=15762817 |url=https://www.psychiatrist.com/pcc/addiction/substance-use-disorders/benzodiazepine-abuse-dependence/ |access-date=5 September 2013}}</ref><ref>{{cite web|url=https://www.drugs.com/pro/alprazolam.html|title=Alprazolam – FDA prescribing information, side effects and uses|website=Drugs.com|access-date=28 August 2019}}</ref>|| Intermediate<ref name=OBrien />
|-
| [[Chlordiazepoxide]] || {{nts|10}}–30<ref name=OBrien /> || Intermediate<ref name=OBrien />
|-
| [[Clonazepam]] || {{nts|19}}–60<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Diazepam]] || {{nts|20}}–80<ref name=OBrien /> || Fast<ref name=OBrien />
|-
| [[Flunitrazepam]] || {{nts|18}}–26 || Fast
|-
| [[Lorazepam]] || {{nts|10}}–20<ref name=OBrien /> || Intermediate<ref name=OBrien />
|-
| [[Midazolam]] || {{nts|1.5}}–2.5<ref name=medsafe2012>{{cite web|url=http://www.medsafe.govt.nz/profs/datasheet/m/MidazolaminjPfizer.pdf|title=Midazolam Injection|website=[[Medsafe]]|publisher=New Zealand [[Ministry of Health (New Zealand)|Ministry of Health]]|access-date=6 April 2016|date=26 October 2012|url-status=dead|archive-url=https://web.archive.org/web/20160222123316/http://www.medsafe.govt.nz/profs/datasheet/m/MidazolaminjPfizer.pdf|archive-date=22 February 2016}}</ref> || Fast
|-
| [[Oxazepam]] || {{nts|5}}–10<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Prazepam]] || {{nts|50}}–200<ref name=OBrien /> || Slow<ref name=OBrien />
|-
| [[Triazolam]] || {{nts|1.5}} || Fast
|}
A benzodiazepine can be placed into one of three groups by its [[elimination half-life]], or time it takes for the body to eliminate half of the dose.<ref name="Cardinali_2006">{{cite book |veditors=Pandi-Perumal SR, Monti JM |vauthors=Cardinali DP, Monti JM |title=Clinical pharmacology of sleep |date=2006 |publisher=Birkhäuser |location=Basel |isbn=978-3-7643-7440-2 |pages=211–213 |chapter=Chronopharmacology and its implication to the pharmacology of sleep |chapter-url=https://books.google.com/books?id=nmG8Dyjzwu4C&q=benzodiazepines%20short%20intermediate%20long%20acting&pg=PA212}}</ref> Some benzodiazepines have long-acting [[active metabolites]], such as diazepam and chlordiazepoxide, which are metabolised into [[desmethyldiazepam]]. Desmethyldiazepam has a half-life of 36–200 hours, and flurazepam, with the main active metabolite of desalkylflurazepam, with a half-life of 40–250 hours. These long-acting metabolites are [[partial agonists]].<ref name=sddat>{{cite book |vauthors=Dikeos DG, Theleritis CG, Soldatos CR |chapter=Benzodiazepines: effects on sleep |pages=220–222 |title=Sleep Disorders: Diagnosis and Therapeutics |veditors=Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ |publisher=Informa Healthcare |year=2008 |isbn=978-0-415-43818-6}}</ref><ref name="manual" />
* Short-acting compounds have a median half-life of 1–12 hours. They have few residual effects if taken before bedtime, [[rebound insomnia]] may occur upon discontinuation, and they might cause daytime withdrawal symptoms such as next day [[rebound anxiety]] with prolonged usage. Examples are [[brotizolam]], [[midazolam]], and [[triazolam]].
* Intermediate-acting compounds have a median half-life of 12–40 hours. They may have some residual effects in the first half of the day if used as a [[hypnotic]]. Rebound insomnia, however, is more common upon discontinuation of intermediate-acting benzodiazepines than longer-acting benzodiazepines. Examples are [[alprazolam]], [[estazolam]], [[flunitrazepam]], [[clonazepam]], [[lormetazepam]], [[lorazepam]], [[nitrazepam]], and [[temazepam]].
* Long-acting compounds have a half-life of 40–250 hours. They have a risk of accumulation in the elderly and in individuals with severely impaired liver function, but they have a reduced severity of [[rebound effects]] and [[Drug withdrawal|withdrawal]]. Examples are [[diazepam]], [[clorazepate]], [[chlordiazepoxide]], and [[flurazepam]].